Meso 2,3-dimercaptosuccinic acid (DMSA) is a compound analogous to 2,3-dimercaptopropanol (BAL). In contrast to BAL however, DMSA is less toxic, has greater water solubility, limited lipid solubility, and is effective when given orally. (Fund. Appl. Tox 11:715-722 (1988)).
Methods to prepare DMSA are known. For example, acetylene dicarboxylic acid can be reacted with thiolacetic acid or sodium thiosulfate to produce an intermediate which can be hydrolyzed to yield crude DMSA. See e.g., U.S. Pat. No. 4,550,193. Crystalline DMSA is typically obtained by crystallizing crude DMSA from, an alcohol, e.g., methanol and ethanol.
2,3-Dimercaptosuccinic acid exists in two forms, the meso form and the DL form. Because meso-DMSA is easier to synthesize and purify, it is more readily available, and has been used in most published investigations and is the subject of this patent application. Meso-DMSA is sparingly soluble and must be titrated to approximately pH 5.5 to go into solution, or dissolved in 5% NaHCO.sub.3. The DL form on the other hand, is readily soluble in distilled water. (Ann. Rev. Pharmacol. Toxicol. 23:193-125 (1983)). As used in this invention, the abbreviation "DMSA", unless otherwise stated, refers to the meso forms. DMSA is available from a variety of biochemical specialty firms.
DMSA was originally introduced by Friedheim and DaSilva in 1954 to promote uptake of antimony during schistosomiasis therapy (J. Pharm. Exp. Therap. 246:84 (1988)), and was first recognized as an antidote for heavy metal toxicity by Liang et al. in 1957 (Acta Physiol. Sin. 21:24-32 (1957)). Since then, DMSA has been shown to remove toxic forms of lead, mercury and arsenic from the body via urinary excretion, presumably by forming water-soluble metal complexes or chelates (Anal. Biochem. 160:217-226 (1987)).
DMSA has been shown to have variable success as an antidote for other toxicities. DMSA was reported to be effective at reducing the concentration of aluminum in the liver, spleen and kidney (Res. Com. Chem. Pathol. Pharm. 53:93-104 (1986)), reducing the concentration of cobalt in the liver, brain, heart and blood (Arch. Toxicol. 58:278-281 (1986)), and as an antagonist for acute oral cadmium chloride intoxication by increasing the urinary elimination of cadmium (Tox. Appl. Pharm. 66:361-367 (1982)). DMSA however, did not increase urinary and fecal excretion of cobalt (Arch. Toxicol. 58:278-281 (1986)), and showed lower efficacy than other chelating agents as an antidote for zinc poisoning (Arch. Toxicol. 61:321-323 (1988)). (See Ann. Rev. Pharm. Toxicol. 23:193-215 (183) for a review of the success and failure of DMSA in treating toxicities).
DMSA has also been labeled with .sup.99 Tc for use in renal scanning (J. Nucl. Med. 16:28-32 (1973), tumor detection (Clin. Otalary 12:405-411 (1987); Clin. Nucl. Med. 13:159-165 (1988)) and for imaging myocardial infarcts (Clin. Nucl. Med. 12:514-518 (1987)).
Recently, administration of DMSA has been used as a treatment for pediatric lead poisoning. Associated with DMSA, is a strong objectionable sulfidic odor. An objectionable odor is generally undesirable, particularly with a product having pharmaceutical utility and oral activity such as DMSA. For compounds administered orally, some degree of voluntary compliance is required and an objectionable odor can negatively impact on patient compliance particularly in pediatric applications.
It is therefore an object of the present invention to provide a low odor DMSA suitable for adult and pediatric oral administration.